The cellular mechanisms that mediate long-term "adaptive" alterations in respiratory neuronal function such as those that occur during acclimatization to chronic hypoxia are not well understood. Research in this area has been limited, for the most part, to mere description. In the proposed studies, the phenomenon of long-lasting facilitation of respiration, an enhancement of respiration that lasts for hours (and possibly days) following stimulation of either carotid body afferents or medullary raphe nuclei, is used as a model to study the cellular manifestations responsible for mediating adaptation in respiratory neurons. The present research is designed to test the hypothesis that long-lasting facilitation is mediated by a combination of transmitter- and genomic- related mechanisms. Electrophysiological, combination of transmitter- and genomic-related mechanisms. Electrophysiological, microdialysis and pharmacological experiments are performed in anesthetized whole animal preparations. Investigations of neurotransmitters and peptide effects on membrane properties are performed in thin tissue sections. Specific aims are: 1) to study the effect if stimulus frequency and duration on induction and maintenance of long-lasting facilitation of respiration, 2) to determine if persistent release of 5-HT in involved in mediating long- lasting facilitation of respiration, 3) to identify 5-HT receptor subtypes that mediate the long-lasting facilitation of respiration, 4) to study in vitro the effects of 5-HT, given alone and in conjunction with a coexisting peptide, on membrane properties of neurons in NTS, phrenic nucleus and other respiratory areas, 5) to determine if long-lasting facilitation of respiration requires gene expression and de novo protein synthesis, 6) to determine if gene expression for 5-HT receptor subtypes in NTS and for peptides and synthesizing enzymes for transmitters in the petrosal ganglia and medullary raphe complex is altered by chronic hypoxia. Findings from these studies should provide the ground work for understanding the cellular and molecular mechanisms that mediate the phenomenon of adaptation in respiratory neurons. When faced with an environmental stress, internal or external, adaptation ensures homeostasis and therefore survival of the organism.